Raynaud""s Phenomenon is one example of a disease that involves deleterious vasoconstriction of the small arteries and/or arterioles of one or more organs of a subject""s body. Raynaud""s Phenomenon is an abnormal vasoreactive response to cold or emotional stress of the small arteries and arterioles in the subject""s digits. Individuals who suffer from Raynaud""s Phenomenon experience episodic, sharp, demarcated, cutaneous pallor and cyanosis of their digits. These symptoms result from spasm or closure of the digital arteries. The condition is painful and debilitating. Under severe conditions, it can even lead to digital ulcers or amputation of the affected digit.
Another, more problematic disease that is associated with a deleterious vasoconstriction of the small arteries and arterioles in one or more organs of a subject""s body is Scleroderma. Scleroderma is a devastating disease of unknown etiology or origin that is associated with severe morbidity and mortality. Vascular dysfunction is an important early defect in Scleroderma (SSc). Raynaud""s phenomenon is one of the earliest manifestations of SSc, occurring in approximately 95% of patients. In addition to the digital arteries, reversible vasospasm also occurs in the terminal arterial supply of the kidney, heart, lung, and gastrointestinal tract of patients with scleroderma. Such vasospastic activity causes ischemia, reperfusion injury and increased oxidant stress of the affected organs and is thought to thereby contribute to endothelial injury and the vascular and extravascular lesions that subsequently occur in this disease. The vascular lesions are found in the small arteries, arterioles (50-500xcexc in diameter) and the microcirculation of the affected organ and are characterized by concentric intimal thickening and adventitial fibrosis of the small arteries and arterioles. The loss of function and structure of the affected blood vessels leads to ischemia of the organ supplied by these vessels, organ failure, and death.
At present there is no cure and no effective therapy for the diseases that involve deleterious vasoconstriction of the small arteries and arterioles, including scleroderma. In addition, there is no therapy that is specifically targeted to Raynaud""s phenomenon. Current therapy for this condition is limited to broad spectrum vasodilator therapy which affects every blood vessel of the treated individual and, thus, causes significant side effects, such as dizziness, nausea, and severe headaches, vasodilator therapy could also exacerbate the problem by directing blood away from the affected organ.
Accordingly, it is desirable to have new methods and pharmaceutical compositions which can be used to treat diseases that involve deleterious vasonstriction of the small arteries and arterioles, including Raynaud""s Phenomenon and scleroderma. Methods and pharmaceutical composition which do not cause systemic vasodilation are especially desirable.
The present invention provides methods for treating diseases associated with deleterious vasoconstriction of the small arteries and arterioles of one or more organs or parts of a patient""s body. In one embodiment, the method comprises administering a therapeutically effective amount of an antagonist to the xcex12C-adrenergic receptor (xcex12C-AR) to a patient with Raynaud""s Phenomenon. Such method is used to ameliorate the cold-induced or stress-induced vasoreactive response that is associated with Raynaud""s Phenomenon. The xcex12C-AR antagonist is administered to the subject either prior to or after exposure of the patient to the cold or to stress. Preferably, the antagonist is administered orally or in a topical composition. To prevent or reduce the extent of the vasoconstriction that occurs when such patient is exposed to stress or cold, the xcex12C-AR antagonist is administered to the patient prior to such exposure. Such treatment serves to maintain, at least in part, blood flow through the cutaneous microcirculation of a patient with primary or secondary Raynaud""s phenomenon. To reverse or lessen the cold induced or stress-induced vasoconstriction of the cutaneous arterial circulation in such patient, the xcex12C-AR antagonist is administered to the patient after exposure to the cold or to the stress. Such treatment serves to restore, at least partially, blood flow through the cutaneous arterial circulation of the treated patient.
In another embodiment, the method is used to reduce the extent of deleterious vasoconstriction that occurs in the small arteries, arterioles, and microcirculation of the lungs, heart, kidneys, skin, or gastrointestinal tract of a patient, particularly a scleroderma patient. The method comprises administering a therapeutically effective amount of an xcex12C-AR antagonist to a patient who is in need of the same. Such treatment serves to maintain or restore, at least in part, blood flow through the small arteries, arterioles, and microcirculation of the lungs, heart, kidneys, skin, and/or gastrointestinal tract in a such patient.
The present invention also provides methods and compositions for studying vasoconstriction in other disease states such as pulmonary hypertension, renal ischemia, gastrointestinal ischemia, and coronary ischemia hypertension, and for studying the physiology of vasoconstriction.
The present invention also relates to a pharmaceutical compositions comprising an xcex12C-AR antagonist and a pharmaceutically acceptable carrier.